Acetylation of lysine residues on histones H3 and H4 results in the loose and active chromatin, which allows various transcription factors to access the promoters of target genes. On the contrary, deacetylation of lysine residues results in a highly compact and transcriptionally inactive chromatin. (Jenuwein, T. & Allis, C. D. Science 2001, 293, 1074.) The levels of histone acetylation and deacetylation are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). (Peserico, A. & Simone, C. J. Biomed. Biotechnol. 2011, 371832.) HDAC overexpression is found in a variety of human cancers, including myeloid neoplasia and solid tumors. (Witt, O. et al. Cancer Lett. 2009, 277, 8.) The association of HDACs with oncogenic DNA-binding fusion proteins or other repressive transcription factors leads to constitutive suppression of specific tumor suppressor genes. (Bolden, J. E. et al. Nature Rev. Drug Discovery 2006, 5, 769.) Therefore, HDACs represent a potential target for cancer treatment.
Statins can reduce serum cholesterol levels through competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR), the rate-limiting enzyme in cholesterol biosynthesis. This effect contributes to their decrease in the incidence of cardiovascular and cerebrovascular disorders, and their remarkable prevention of cardiovascular disease (CVD). (Ward, M. M. F1000 Medicine Reports 2009, 1, 35. Kapur, N. K. Expert Rev. Cardiovasc. Ther. 2007, 5, 161.) Statins possess an established record of human safety and efficacy in CVD prevention and also show promise for cancer prevention in observational, preclinical, and certain aspects of randomized controlled studies. (Hawk, E. & Viner, J. L. New Engl. J. Med. 2005, 352, 2238.) Statins also exhibit antitumor activity as shown in both in vitro proliferation and in vivo xenograft model. (Lin, Y. C. et al. Cancer Res. 2008, 68, 2375.)
Combinations of HDAC inhibitors with cytotoxic agents, or targeted anti-cancer drugs have been reported to improve the outcome of cancer treatment in several pre-clinical research and clinical trials. (Lane, A. A. & Chabner, B. A. J. Clin. Oncology 2009, 27, 5459.)
Histone deacetylases (HDACs) represent a potential target for cancer treatment, whereas statins can inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) to reduce serum cholesterol levels.